Summary A central challenge in neuroscience is to develop methods to manipulate specific cell types within the mammalian brain. Recent developments in optogenetics have revolutionized our ability to control the activity of both neurons and non-neuronal cells. However, this approach suffers from one drawback, the difficulty in delivery light stimulus to target cells that are located deep within the brain or the body. The Chalasani lab has recently demonstrated a noninvasive method to control the activity of neurons. They have identified a pore- forming subunit of a mechanosensitive channel (TRP-4) that responds to low-intensity ultrasound. Further, they showed that expressing this channel is specific cells renders those target cells sensitive to mechanical deformations generated by noninvasive ultrasound waves. This proposal aims to develop this approach (they have termed ?sonogenetics?) to control specific cells within the mouse brain. Further, they find that this approach can be used to control the activity of mammalian neurons in vitro. They plan on using a high- throughput assay system to test whether other members of the TRP-N family are sensitive to ultrasound pulses. Additionally, they will also analyze whether altering the number of ankyrin repeats affects the ultrasound responsiveness of these channels (consistent with a recent study showing similar results in the Drosophila TRP-N channel) (Aim 1). They also plan on developing a new head device with a slot for a tiny, lightweight ultrasound transducer to deliver ultrasound stimulus to the mouse brain (Aim 2). Finally, they will test the efficacy of the sonogenetic approach in vivo using electrophysiological and behavioral analysis. They will express TRP-4 or other mechanosensitive channels in cortical PV interneurons, striatal D1 or D2 medium spiny projection neurons and control their activity in vivo. Optogenetic methods have been previously used to control these cell populations providing benchmarks for comparison. These studies will develop a noninvasive method to manipulate the activity of specific cells within the rodent brain or its body. Further, these methods can be translated into the human to target specific cell populations for therapeutic purposes.